Chelate compounds and process for their preparation



United States Patent omce 3,391,176 Patented July 2, 1968 66 5 Claims.(Cl. 260-448) ABSTRACT OF THE DISCLOSURE Chelate compounds of aluminum,magnesium, iron or calcium containing a salicylate bidentate ion or a 5-hydroxy salicylate ion with or Without bidentate ions formed fromcertain mono-carboxylic alpha-hydroxy acids or tetradentate ions formedfrom tartaric acid or citric acid and also containing magnesium,calcium, sodium, potassium or ammonium radicals. The compounds areintended for use in analgesic and antipyretic preparations.

CROSS REFERENCE TO RELATED APPLICATIONS This is a continuationin-part ofmy copending application Ser. No. 274,936 filed Apr. 23, 1963, nowabandoned, which is a continuation-in-part of my application Ser. No.47,371 filed Aug. 4, 1960 (now abandoned).

BACKGROUND OF THE INVENTION This invention relates to pharmaceuticalcompositions and is particularly concerned with chelate complexes ofsalicylic acid and/or acetylsalicylic acid (aspirin) or gentisic acid,either alone or in association with gluconic acid or other alpha-hydroxyacids and with various metals.

The novel compounds are intended for use in analgesic andantipyreticpreparations, which are employed to relieve headaches, muscular andneuritic pains and in the treatment of rheumatism.

It is a disadvantage of the oral administration of aspirin that it hasan irritant effect on the gastric mucosa, although its action is muchless severe than that of salicylic acidexcept in susceptible persons.Acetylsalicylic acid has come under increasingly severe criticism sinceevidence was found of gastric lesions and localized hyperaemia due tocontact of particles of aspirin with the gastric mucosal wall. Thehaemorrhagic propensities of aspirin impose a particularly seriouslimitation on its use as an antirheumatic and uricosuric agent as, inthe treatment of rheumatism and related conditions, the dosage needs tobe high and prolonged.

It is an object of the present invention to provide compounds whichpossess the analgesic and other therapeutic properties of aspirin whilehaving a bland effect on the oral and gastric mucosa.

It is known that sodium gluconatoaluminates and chelatedhydroxoaluminates of other alpha-hydroxy acids may be used as solublebuffer antacids in the treatment of gastric hyperacidity.

It has now been found that in these compounds gluconic acid may bereplaced wholly or in part (according to the compound) by aspirin,salicylic acid or gentisic acid. Compounds may be prepared in whichvaried molar ratios of salicylic, acetylsalicylic or gentisic acid togluconic acid are employed. Examination of the compounds prepared fromaspirin indicates that they are salicylato complexes in which theaspirin has been deacetylated, the displaced acetyl radical beingco-ordinated to the aluminium (or other central metal ion), replacing ahydroxo group.

In suitable compounds the chelating acid may be wholly salicylic acid oracetylsalicylic acid, but these compounds are only stable either (a)under highly alkaline conditions, existing in the presence of excesshydroxyl ion or (b) when part of the chelating ligand is present in thesimple form in which the hydroxyl group has not lost its proton, e.g.when it is present as excess sodium salicylate.

The aluminium salicylato chelates apparently exist only in the presenceof excess hydroxyl ion or chelating acid ionic species and we found thatas little as 5% gluconic acid (in the form of gluconatoaluminate) orother suitable alphahydroxy acid (as chelates aluminate) stabilizes thesalicylato aluminate and enables it to be produced in solid form.

The stability of the mixed salicylato-gluconatoaluminates withoutemploying excess alkali hydroxide and at approximately neutral pH (ofExample 3), together with the high solubility of many of thesepreparations, is in marked contrast to the properties of the salicylatocompounds alone and this is an important :feature of the invention.

In addition to being analgesic compounds, the substances are alsoantacids and generally it is desirable to incorporate higher proportionsof gluconic acid (or other non-salicylate hydroxy acid) than is presentin the 19 to 1 ratio compound, in order both to increase the solubilityof the compound and to ensure that a quantity of the preparationcontaining 5 to 10 grains of aspirin should exert a significantbuffering action on acid gastric juice.

Provided the ratio of salicylic acid to gluconic acid is not too high,the compounds are very highly soluble and may have a nearly neutral pHreaction. One of the 4 to 1 aspirin to gluconic acid compounds, forexample, has a solubility of the order of 50% w./w. (c. w./v.) and thepH of a 30% w./v. solution is 6.6. A preparation of the 1 to 1 aspirinto gluconic acid compound may be manufactured to provide, for example, 5or 7.5 grains of aspirin to the teaspoonful (4 ml.) dose.

When one or two teaspoonfuls (from 5 to 15 grains of aspirin) are addedto a simulated gastric pool of ml. N/ 10 hydrochloric acid, the pH israised to between 3 and 4.5. Salicylic acid can be obtained from theclear solution by benzene extraction; by contrast, when equivalentamounts of sodium salicylate are added. to a similar pool of acid,copious and coarse precipitates of salicylic acid are obtained. Withcompounds according to the present invention, with salicylic acid insolution at a pH of 3 to 4, local action should be bland and absorptionshould be rapid.

These expectations have been substantiated by animal tests, whichindicate that the compounds have analgesic potency equivalent to theiraspirin contents and that they do not cause any gastrointestinalhaemorrhage. Some of the compounds of the invention and theirpreparations are very stable and this is in contrast to various knowneffervescent preparations intended to form sodium aspirin by reactionduring dissolution. These preparations are susceptible to hydrolysis ofthe aspirin component during storage, often leading to complete loss ofreactivity of the effervescent vehicle, and to loss of palatability,resulting from the presence of the irritant free salicylic acid andacetic acid.

In addition to the sodium salicylatohydroxoaluminates it has been foundthat salicylatohydroxo metal chelates may be prepared, in which calciumand magnesium are substituted for aluminium.

SUMMARY OF THE INVENTION The present invention provides compounds of thegeneral formula:

and dimers thereof, wherein M is magnesium, calcium, sodium, potassiumor the ammonium radical, M is aluminium, magnesium, iron or calcium, andA is the salicylato bidentate ion:

or the S-hydroxysalicyato ion, either alone or together with an ion orions selected from the group consisting of the bidentate ions formedfrom the monocarboxylic alphahydroxy acids of the formula:

ikiilli in which R is CH 0r C H O and the tetraclentate ions formed fromtartaric and citric acids of the respective formulae:

t 0 o r CH. \OCII 0iio 04511 and o I CH5 0-0=o wherein x is an integerfrom 1 to 5 inclusive, y is unity for bidentate ions and 2 fortetradentate ions, w is an integer from 0 to 4 inclusive, 2 is aninteger from 1 to 4 inclusive, n is 2 for bidentate ions when thevalency of M is greater than 1 and is unity in all other cases, I is thevalency of M divided by n, m is the valency of M and v is an integerfrom 0 to 6 inclusive.

When A0 is a mixture of ions, it is to be understood that either amixture of chelating acid ions in the complex anions or a mixture ofcomplex anions is referred to. The phenomenon of polymerisation byolation is well known and the type of reaction involved may berepresented as follows: 7

It will be seen that the reaction involves the elimination of aquogroups co-ordinated to the aluminium ions in the monomer (or aluminiumions at the end of the chain in the continued process of olation). Thedisplaced water molecules may remain in outer spheres of the aluminiumions however. Thus, in Example 3 following, the cryoscopic estimation ofaverage ionic weight indicates a dimer, but the ash result is inslightly closer agreement with a molecular weight indicative of waterretention at the level of the monomer.

Furthermore, water equivalent to that expected to be removed fromcoordination sites in forming the dimer is lost from the compound at atemperature of C., while the remaining water is not lost until asignificantly higher temperature is reached. This trend has also beennoted with the higher polymers of chelated gluconatoaluminates. With themixed salicylato and gluconato compounds the cryoscopic estimations showthat many of the l to l salicylic acid to gluconic acid compounds aredimers, while the 4 to 1 ratio and higher ratio compounds examined aremonomers.

In the major salicylato complexes of practical interest, the ratio ofchelating acid to metal is l to l, or not much higher, and with thisratio the co-ordination number of aluminium is six.

As with the wholly gluconatoaluminates, it is found that solution ofmixed salicylatogluconato compounds are almost completely non-astringentto the oral mucosa, indicating the virtual absence of free aluminiumions. Other evidence of complex formation includes:

(1) Many of the compounds are of high solubility which is in strikingcontrast to the insolubility of aluminium salicylate and aluminiumaspirin, and the relatively low solubilities of aspirin and salicylicacid.

(2) No precipitates are produced at pH 10, when ammonium chloride andammonium hydroxide are added to solutions of the compounds, at least inthe concentration range 0.02 to 0.1 M. Similarly, clear solutionsresult, in most cases, when sodium fluoride is added to solutions of thecompounds in the same concentration range.

(3) Cryoscopie estimations of molecular weights indicate clearly thatthe solutions do not comprise mixtures of simple ions which would havelow average ionic weights. These determinations, and the other assaydata are in good agreement with the formulae assigned to the compounds.

Cryoscopic estimations of average ionic weights and assay data incomparison with expected values for several of the examples are shown inTable I.

STRUCTURE In the light of the cryoscopic and assay data the structuresof the compounds described in the application are considered to be ofthe following types:

(i) All salicylato monomer (a component of the products of Examples 1, 2and 4).

Sodium saiicylatodihydroxyaluminate III (ii) Structure of a mixedsalicylato gluconato dimer (Example 3).

TABLE I.C RYOSCOPIC AND ASSAY DATA [For examples 1 to 5(a)] Average Losson ASSAY, percent Example State of Polymerlsation Observed or IonicDrying 60 (cryoscopic) Expected Weight in vacuo Ash 2 N 21 Al SaligglicAcetic acid Mg Observed. 145.0 1. 74 37.3 11. 3 8. 72 1 Momm Plus Dlmer-{lligpecteg 141.0 2. s4 5 8. 1

serve 134. l 3. 1 6 7. 2 Mmmmer {Expected 139. 2. 9 28. s 9. o 8.8 3Dimer {Observed 181.8 6. 14 28.0 9.2 8. 1

""""""""""""""""" g p g m .2 8 2-3 i 'i serve .1 104. .5 4 {Expected108.0 1. 7 3e. 1 12.8 10. 0 e) 1 .233833: 53:? 33:33:11: I+ lf" 1 Noassay data for gluconic acid are shown. A method is available butsalicylic acid seems to interfere.

2 Na2O+A120 or Mg0+ excess alkali as NazCOg.

Sodium: This was precipitated and estimated as sodium magnesium uranylacetate.

Aluminium: The compounds were wet ashed and aluminum was de termined bythe method of the British Pharmacopoeia for aluminium hydroxide gel.

(iii 0 0 o Na H 0 A1 0H Disodiumsalicylatogluconatodihydroxodiaque'a-dioldialum inate III R=C4HDO tocomplete CGHIOO'I, the glnconato ligand. The compound octasodiumtetrakis(gluconato)bis(sali cylato),u. diacetatodialuminate IIIdihydrate of the forhas been found to have specially valuablepharmacological properties.

Preferably, Compound I is prepared by reacting sodium aluminate withgluconic acid, and then reacting the product with acetylsalicylic acid.

Compound I has the following characteristics:

Molecular weight=l440.788

Average ionic weight (9 ions) 160.09

Average ionic weight estimated by cryoscopic means:

Ash (Al O -l-Na O) calculated=24.9l% (dry basis) Ash (Al O +Na O)obse-rvecl=26.40% (dry basis) The empirical formula (dry monomer) is:

NE14AlC21H27O 9, which is equivalent to Molecular weight=702.379

Aluminium content=3.84% Al (dry basis) Sodium content=l3.09% Na (drybasis) Magnesium: Estimated by complcxometric (volumetric) assay afterashing the compounds and dissolution in acid.

Salicylic Acid: Extracted from acid solution with chloroform which wasthen evaporated oil in the presence of a little ferric alum ammoniummonochloracetate bufier. More buffer was added and the optical densitymeasured at 530 my.

Acetic Acid: Distilled from a sulphuric acid solution into standardalkali and back titrated. Distillate checked for salicylic acid.

sodium salicylate and are comparable with those for aspirin.

Tests for antipyretic activity were carried out in rabbits, which wereobserved over periods of 90 minutes by means of rectal thermocouplesand, provided that the individual temperatures did not deviate by morethan 0.2 C., the rabbits were dosed intragastrically with 1 mM./kg. oftest compound and intravenously with 0.5 ,rlg. Shigella endotoxin. Thetemperatures were recorded for a further 5 /2 hours. Each of twelverabbits received Compound I, sodium salicylate and control solution on across-over basis over a period of 9 weeks. Antipyretic activity wascalculated as the differences between control and test areas under thetemperature/ time plots.

This showed 50% antipyrexia for Compound I and 32% for sodiumsalicylate. Results for aspirin in previous tests were 52% and 43%.

Biochemical studies were carried out with Compound I, with sodiumsalicylate and acetylsalicylic acid as comparison compounds as follows:

(1) Salicylate levels in blood plasma and urine were determined atvarious times between /2. and 24 hours in Corgi dogs, after oral dosagewith Compound I.

Plasma salicylate levels in humans were determined between 15 minutesand 3 /2 hours after oral administration of Compound I.

Urinary excretion was studied up to 54 hours after dosage. Salicylatelevels in both urine and blood were compared with those obtained afterdosage with sodium salicylate and acetylsalicylic acid.

(a) Dogs.Pernbrokeshire Corgis were dosed orally on the basis ofapproximately equal salicylate content with encapsulated Compound I (400rug/kg), sodium salicylate mg./ kg.) and acetylsalicylic acid mg/kg) ina cross-over test.

Blood samples were drawn from a forelimb vein, heparinised andcentrifuged. The plasma was removed and stored at approximately -20 C.overnight. Dogs were kept individually in metabolism cages and the urinecollected over a period of 24 hours in flasks cooled with cardicc solidCO Plasma salicylate levels in dogs showed all three compounds to havesimilar absorption patterns with a flattened peak plasma level ofbetween and g. salicylate per ml. plasma, two to four hours afterdosage.

The first series of experiments using eight dogs provided blood levelsup to eight hours after dosing. A second series using four animalsshowed that plasma levels after all three compounds declined onlyslowly. Thus at 12 hours, levels of 106 to 132 pg. salicylate per ml.plasma were recorded and after 24 hours 36 to 47 ,ag.

In general there was no consistent trend in the differences between freeand total salicylate levels. Small differences of possible significancewere seen in the plasma levels shortly after dosing with Compound I andwith acetylsalicylic acid. Thus the plasma levels at half an 7 hourindicated the presence of some conjugated salicylate, both afteracetylsalicylic acid and Compound I (10% of the total salicylate levelin each case). Again at one hour the circulating level of conjugates wassimilar both after acetylsalicylic acid (11% of the total salicylatelevel) and Compound I (15% of the total level).

Comparable values for total urinary salicylate after dosing withCompound I or sodium salicylate were obtained from each collectionperiod. After acetylsalicylic acid however elimination was delayed, thetotal salicylate appearing between 6 and 24 hours being more than twicethe to 6 level.

(b) Humans-The subjects took on different occasions Compound I, sodiumsalicylate and acetylsalicylic acid in 50 ml. aqueous solutioncontaining the equivalent of 500 mg. salicylate.

Blood samples were drawn from the ante-cubital vein at times between 15minutes and 3 /2 hours after dosing. The samples were collected inheparinised tubes, centrifuged and the separated plasma stored at -20 C.overnight.

The total urine output was collected separately in the two periods 0 to6 hours and 6 to 24 hours following dosage.

Absorption of all three compounds in humans from solution was rapid.Peak plasma levels following Compound I or sodium salicylate wereachieved 15 minutes after administration, while after acetylsalicylicacid the peak occurred at one hour. Compound I appeared to be absorbedappreciably faster than acetylsalicylic acid, but only marginally fasterthan sodium salicylate. One hour after dosage the salicylate levelsproduced by all three compounds were very similar. Differences betweenfree and total salicylate levels were seen 15 minutes after bothCompound I (7% of the total level) and acetylsalicylic acid (24% oftotal), but not following sodium salicylate. At one hour there was asignificant difference only after acetylsalicylic acid (14% of totalsalicylate).

Thus Compound I was absorbed rapidly, some conjugated salicylate beingpresent in the plasma at 15 minutes but none at one hour.

The excretion patterns of all three compounds were similar, althoughsome quantitative differences were observed. With each compound over 98%of the salicylate excreted appeared within 24 hours. After completehydrolysis of metabolites, however, only some 50% of the administereddose was recovered within 54 hours.

The excretion pattern of Compound I more closely resembled that ofacetylsalicyclic acid than of sodium salicylate. After Compound I,however, the total amount of conjugates excreted was slightly greater inthe 0-6 hour period compared to acetylsalicyclic acid and slightly lessin the 6-24 hour period. The quantitative metabolism of sodiumsalicylate differed slightly from that of the other two compounds. Theamount of alkali labile conjugates excreted after sodium salicylatedosage was lower and the amount of acid-labile conjugates proportionallyhigher than after either Compound I or acetylsalicyclic acid.

(2) Using radioactive chromium-51 tagged red blood cells, the volumes ofoccult blood excreted after oral dosing of dogs with Compound I at threedose levels was determined. These blood losses were compared with thoseproduced after dosing with acetylsalicyclic acid and sodium salicylateand with undosed control animals.

The principle of the method consists in labelling the circulating redblood cells with radioactive chromium-51 and subsequently measuring andcomparing the radioactivity of the faeces and samples of venous bloodwhich are withdrawn during the course of the experiment.

The method used for labelling the red blood cells was based on hat ofBannerman (1957, Brit. Med. J. 2, 1032), who applied the method tomeasure the faecal blood loss in humans.

Pedigree Beagles were used for these studies. A summary of the resultsobtained is as follows:

Dosage with Compound I at the near toxic level of 1500 mg./kg. daily for28 days (equivalent to 391 mg./kg. of acetylsalicyclic acid, i.e. grainsof acetylsalicylic acid every 6 hours to a 50 kg. man) produced asignificant increase in gastro-intestinal blood loss similar to thatproduced by mg./kg. daily of acetylsalicylic acid. At doses of 1000mg./kg. and 400 mg./kg., however, Compound I did not produce anysignificant faecal blood loss.

Using the radioactive chromium-51 tagged red blood cell technique, testswere made in human volunteers.

Initially, six subjects were given Compound I in a dose equivalent to 10gr. of acetylsalicylic acid three times daily before meals for a totalof 5 days. The blood loss in the stools was measured for a period beforethe 5 days of treatment and measurements were continued until shortlyafter the end of treatment.

Twelve subjects were then given larger doses of Compound I equivalent to20 gr. of acetylsalicylic acid three times daily. A 5 day course wasfollowed after a drug free interval of two days by a 5 day course ofacetylsalicyclic acid, 20 gr. three times daily being given. In twocases the order of taking the drugs was deliberately reversed. Theadministration of high doses of drugs on an empty stomach was intendedto provide a severe test of each drugs liability to cause intestinalbleeding.

Intestinal bleeding was negligible or absent in all subjects whoreceived Compound I with a single exception, this subject havingreceived acetylsalicyclic acid for 5 days prior to taking Compound I. Hebled heavily during this time and continued to bleed to a diminishingextent when he took Compound I during the following Week.

Bleeding was attributed, in this case, to the after effects ofacetylsalicylic acid. A similar, but less marked bleeding alwaysfollowed large dose acetylsalicylic acid administration. Compound I hadclear and obvious advantages over acetylsalicylic acid in this respect.

It had been noted in previous studies that blood loss occurred in everysubject, either during or immediately after acetylsalicyclic acidadministration.

The invention also provides a pharmaceutical composition comprisingCompound I, together with a pharmaceutically acceptable carrier.

The compositions are preferably intended for oral administration intablets, syrups, granular preparations and similar forms, in which theusual additives, excipients, colouring, flavouring and other materialsare included.

The high solubility and freedom from astringency enables palatable syruppreparations and effervescent mixtures to be made as described in someof the examples.

Description of the prepared embodiments:

Example 1 The preparation of a mixed acetato salicylato/gluconatoaluminate in which the ratio of aluminium to acids is as 1:0.5; 0.5.

MATERIALS USED Dry sodium aluminate 93.8% G.

(Na O:Al O =1.24) 79.27 Aspirin 72.06 Glucono-delta-lactone 71.2 Sodiumhydroxide 8.32

the gluconic acid solution and a small quantity of a filter' aid wasadded. The suspension was then filtered under suction. (NB. The drysodium aluminate contained ironz0.07% Fe O (4) The solution wastransferred to a beaker on a water bath and the aspirin was added withstirring when the temperature was in the range 6070 C.

(5) The sodium hydroxide was dissolved in a little water and added tothe bulk when the aspirin had all dissolved.

(6) The solution was then evaporated to dryness in vacuo at 60 C.

AVERAGE FORMULA IN IVIONOMERIC FORIH STRUCTURE (1) Approximate estimateof degree of polymerisation. The cryoscopic estimate of average ionicweight=l45. If x=the number of aluminium ions in the complex anion Thissuggests a salicylato monomer and a gluconato dimer.

(2) The dimer will be 4[- 2 )G( G 1O 'I)2] 2 (The monomer would havehad, originally 1H O per molecule); this leaves for the salicylatocompound: 2Na[Al (0H) (C H o (OH CO0) (H 0) This indicates 9 ions and anaverage ionic weight:

Observed: 145

(3) If 2H O are lost from the gluconato dimer at 60 C. in vacuo thisrepresents:

Observed 1.74

The compound therefore comprises a mixture of 1 moletetrasodiumbisgluconatohexahydroxodialuminate III+2 moles of sodiumsalicylatoacetatohydroxoaluminate III.

PROPERTIES Appearancebiscuit coloured granular solid (NB. colourprobably due to traces of iron) Solubility at 23 C.- 80% w./v.

pH of solutiona 40% w./v. solution has a pH of 10.6

Example 2 A preparation of 4:1 aspirin to gluconic acid chelateshydroxoaluminate. This compound was prepared by a similar procedure tothat given for Example 1, but employing the following quantities of rawmaterials:

G. Dry sodium aluminate 93.8% (Na O:Al- O =1.24) 125 Aspirin 205Glucono-delta-lactone 50 AVERAGE FORMULA IN MONOMERIC FORM The averageionic weight= g g 136.9

STRUCTURE As monomers the species present will be- PROPERTIESAppearance-a pinkish-white granular solid. Solubility at 23C.approximately 65% w./v. pH of solutiona 40% w./v. solution has a pH of6.6

Example 3 A preparation of a mixed salicylato gluconato aluminate ofsimilar aluminium to acids ratio .as in Example 1, but of lower sodiumcontent.

MATERIALS USED Dry sodium aluminate 93.8% G. Na O:Al O =1.24) 125Aspirin 118 Gluconoxlelta-lactone -l"17 The method of preparation wassimilar to that given for Example 1.

AVERAGE FORMULA IN MONOMERIC FORM STRUCTURE.-APPROXIMATE ESTIMATE OFDEGREE OF POLYMERISATION The cryoscopic estimate of average ionicweight=l8 l.8. If x=the number of aluminium ions in the complex anion311x 1.24x-I-1 This result indicates a mixed dimer of average formulaObserved= 181.8

If the 2H O are lost on heat at 60 C. in vacuo the loss in weight willbe Observed loss at 60 C. in vacuo =6.l4%

Average ionic weight= =l79.0

In view of the Na:Al ratio* the components will be PROPERTIESAppearance-light biscuit coloured granular solid Solubility at 23 C.w./v. pH of solutiona 40% w./v. solution has a pH of 6.7

Example 4 The preparation of a mixed salicylato/gluconatoaluminate inwhich the molar ratio of salicyclic acid to gluconic Salicyclic acid26.24 2 Sodium hydroxide 2.08

*The Nils dimer may be prepared by substituting aluminium isopropoxide(or active aluminium hydroxide) for part of the sodium aluminate.

PROCEDURE ('1) The sodium aluminate was dissolved in 50 ml. of waterwith stirring which was continued for 30 minutes.

(2) The glucono-delta-lactone was dissolved in minimal water.

('3) Half the salicylic acid was dissolved in 1 litre of boiling water.

(4) Filtered sodium aluminate solution was poured into a mixture of 100ml. of the salicylic acid solution and all of the gluconic acidsolution.

(5) The solution from stage 4 was added to the rest of the salicylicacid solution gradually, until signs of precipitation of aluminiumhydroxide were noted and at this stage the remaining half of thesalicylic acid was added in solid form. When a clear solution resultedthe remainder of the solution from point 4 was added.

(6) The sodium hydroxide was dissolved in minimal Water and then addedto the bulk of solution. After stirring an almost clear (very slightlytranslucent) solution resulted. Part of the solution was dried in vacuoat 60 C., and another portion was air dried.

AVERAGE FORMULA IN DIONOMERIC FORD/I STRUCTURE-APPROXIMATE DEGREE OFPOLYMERISATION The cryoscopic estimate of average ionic weight=l04.8. ifx represents the number of aluminium ions in the complex anion Thisindicates a monomer.

The compounds present may be represented as where AO=95% salicylato ionand gluconato ion of average weight 139.0. (It is, of course, understoodthat the salicylato aluminates and gluconato aluminates, form separateanions.) Average ionic weight=540.02

108.0 Observed av. ionic weight=104.8

PROPERTIES Appearance-21 buif to pinkish granular solid Solubility at 23C., oven dried material c. 2.5% w./v.;

air dried material c. 7.8% w./v.

pH of solution-the pH of a 2 /2% w./v. solution=10.2.

Example 5(a) The preparation of a mixed acetatosalicylato gluconatomagnesate.

MATERIALS USED Magnesium oxide 10.08

Sodium hydroxide 30.00

Glucono-delta-lactone 44.5

Aspirin 22.52

PROCEDURE AVERAGE FORIMULA IN DIBIERIC FORM 6[ 2 s 10 7)2( gg4%3) s )3]The cryoscopic estimate of average ionic weight is 78.6 which is clearlyless than a monomer, indicating a mixture of ions. Having regard to thecommon coordination number of magnesium of 4, the compounds are likelyto be Such a mixture would have 10 ions and the average ionic weightwould be 82.1. Observed ionic weight =78.6.

Example 5 (b) The preparation described in Example 5a above was repeatedsave that the sodium hydroxide was reduced in amount to 20.00 g. Thiscorresponds to a reduction of 2NaOH and the preparation would beexpected to give a mixture of the two complex compounds with theomission of the surplus sodium hydroxide.

The components, therefore, are expected to be Expected average ionicweight= z =l23jl The solution of this mixture would contain 10 ions ormolecules of average weight=84.7. Observed cryoscopic weight- 82.7.

PROPERTIES Appearance-a White granular solid Solubility at 23 C. l:60%w./v. pH of solution-the pH of the 60% w./v. solution is 11.3.

When a quantity of the mixture containing the equivalent of 10 grains ofaspirin was added to 100 ml. N/ 10 I-ICl no precipitate was formed,while a similar experimentusing an equivalent amount of sodiumsalicylategave a copious precipitate of salicylic acid. No precipitateoccurred with the complex mixture until the strength of the 100 ml. poolof acid was increased to 0.4 N HCl.

Example 6 The preparation of a mixed salicylato gluconato calcate.

MATERIALS USED G. Calcium hydroxide 14.8 Sodium hydroxide 16.0Glucono-delta-lactone 53.4 Salicylic acid 13.8

PROCEDURE The glucono-delta-lactone was dissolved in 200 ml. ofdistilled water and heated to C. Portions of calcium hydroxide andsalicylic acid were added alternately to keep as clear a solution aspossible. Sodium hydroxide was dissolved in about ml. of distilled waterand 13 added to the bulk solution. The solution was then evaporated todryness at 60 C. in vacuo. The materials taken correspond to acomposition:

2[ s 1o 7)2] 2[ a 10 7) 2 4 3)] 474.34- 416.30

Expected average ionic weight=148.44 Observed=9l.3

Again, this result suggests a lower level of complex formation to leavefree sodium hydroxide present, e.g. e 1u 7) 2 )2]+[ 'z 4 a) 2 )2] +2CHOH(CHOH) .COO.Na+2NaOH Again, there are 10 ions or molecules present ofaverage Weight=99.3 Observed cryoscopic result=91.3.

PROPERTIES Appearance-may be concentrated to a clear, almost dry, jelly.The material is insoluble after evaporation to dryness. Solubility at 23C.-- t75% w./v. pH of solution-a 12% w./v. solution has a pH of 11.3.

Example 7 The preparation of a salicylato gluconato magnesate.

MATERIALS USED Magnesium oxide 10.8

Sodium hydroxide 20.01

Glucono-delta-lactone 44.54

Salicylic acid 34.53

PROCEDURE The procedure adopted for this preparation was identical withthat used for Examples a and 5b save that the aspirin employed in thoseexamples was substituted by salicylic acid.

The materials taken correspond to a formula Molecular weight=400.54Average ionic weight: 13 3 .5 1 Observed ionic weight=95.2

Once again, a mixture of less complex species is indicated, e.g.

[ g s io v) 2 0 The presence of 5 ions or molecules in the solution isindicated of average weight=c. 91. Observed cryoscopic weight=95.2.

It is indicated in these preparations that the magnesium and calciumsalicylato chelates with, or without, gluconic acid are stable onlyunder alkaline conditions, i.e. the presence of excess hydroxyl ionleads to a higher level of complex formation. As further evidence ofthis, additional sodium hydroxide was added to a solution of thematerial of Example 7 at the rate of 1 mole NaOH to 1 mole of thecompound of molecular weight 454.6. The following reaction might beexpected to occur:

14 MATERIALS USED Dry sodium aluminate 93.8% G- (Na O:Al O =1.24) 19.07Salicylic acid 82.87 Sodium hydroxide 14.08

Molecular weight=504.25 Average ionic weight=126.06 Observed averageionic weight=l07.8

Once again, the experimental results are in agreement with a lowerdegree of complex formation, viz.

N32 [Al C7H403)2( OH) (H 0) 1 +C H (OH) COO.Na

Or the empirically equivalent:

Na [Al (AO) (AOH) .H O+NaOH These formulations correspond to 5 ions insolution of average weight: 107.9. Observed ionic weight=107.8.

From these results it appears that the wholly aluminium salicylatochelates are only formed in the presence of free hydroxyl ion or at alow level of complex formation where part of the salicylate does notform the bidentate (A0) ion.

As with Example 7, additional sodium hydroxide was added to a solutionof the material of Example 8 at the rate of 1 mole NaOH to 1 mole of thecompound of molecular weight 504.25. The following reaction might beexpected to occur:

Average ionic weight (trisodium trisgluconatoaluminate III-i-NaOH)Observed cryoscopic estimate=88.6

' PROPERTIES Appearancean olT-white granular solid Solubility at 23C.=c. 12% pH of solutionthe pH of a 12% solution is 9.7

Example 9 The preparation of an acetatosalicylatoaluminate.

MATERIALS USED Dry sodium aluminate 93.8% G.

(Na O:A1203=1.24-) Aspirin 36.03 Sodium hydroxide 14.08

Expected average ionic weight= =98.92

Observed cryoscopic ionic weight=98.45

PROPERTIES Appearancewhite granular solid Solubility at 23 C.- l:80%w./v. pH of solutionthe pH of a 53% w./v. solution is 11.35

- Example 8 The preparation of a wholly salicylato aluminate.

PROCEDURE (1) The dry sodium aluminate was dissolved in 100 ml. of waterand filtered to remove iron.

(2) The sodium hydroxide was dissolved in 100 ml.

of water and the whole of the aspirin was then dissolved The materialstaken correspond to a compound of the formula:

Molecular weight=342. 16 Average ionic weight=85 .54 Observed averageionic weight: 54.9

The experimental result may be explained on the basis of a lower degreeof complex formation in the presence of free sodium hydroxide, viz.

[Al (O HiO;) (Cine 0 0x112091 3NaOH This corresponds to 7 ions ormolecules in solution of average weight=56.2. Cryoscopic weight=54.9.

PROPERTIES Appearance--an off-white granular solid with slightly pinktinge. Solubility at 23 C.-approximately 4% pH of solution-the pH of ac. 4% solution is 11.3.

Example The preparation of a hydroxylaluminate chelate composition oftartaric and salicylic acids.

MATERIALS USED G. Dry sodium aluminate 93.8% (Na O:Al O =1.24) 19.07Tartaric acid 15.01 Salicylic acid 13.81

PROCEDURE AVERAGE FORMULA IN MONOMERIC FORM 1.24[ 4 2 6)U.5(;1; ?3)O.5()1.24( 2 )1.76]

STRUCTURE.APPROXIMATE ESTIMATE OF DEGREE OF POLYMERISATION Thecryoscopic estimate of average ionic weight=123. If x=the number ofaluminium ions in the complex anion As the tartrato ligand forms adouble ring the expectation is at least a dimer. The above result,therefore, suggests a tartrato dimer and a salicylato monomer. Theaverage formula is closely equivalent to:

The expected dimer and monomer would be respectively Nag 2 4 2 s)2( z).3]

and

Average ionic weight= Observed cyroscopie weight 122.8

16 7 PROPERTIES Appearancean off-white glassy solid Solubility at 23 C.-i: w./v. pH of solution-a 5 0 w./v. solution has a pH of 9.4

Example 11 The preparation of an ammonium hydroxoaluininate chelatecomposition of citric and salicylic acids.

PROCEDURE (1) The aluminium chloride was dissolved in 200 ml. of waterand ammonium hydroxide .(additional to the amount shown above) was addedto pH 7.

(2) The aluminium hydroxide was filtered ofl? and washed until free ofchloride iron.

(3) The citric acid was dissolved in 300 ml. of water and the freshaluminium hydroxide stirred in. This was dissolved with the aid ofgentle heat.

(4) The ammonium hydroxide was diluted to 50 ml. and added to thesolution of aluminium hydroxide in citric acid.

(5) The solid salicylic acid was added and dissolved with the aid ofheat.

(6) Finally, the solution was evaporated to dryness in vacuo at 60 C.

AVERAGE FORMULA IN MONOMERIC FORM STRUCTURE.APPROXIMATE ESTIMATE OFDEGREE OF POLYMERISATION The cryoscopic estimate of average ionicweight=126.35

If x=the number of aluminium ions in the compleg anion As the citratoligand forms a double ring and a dimer is the lowest expectation, theabove result suggests a citrato dimer and a salicylato monomer, asfollows:

and

2NH4[A1HI(C7H4O3) )z( 2 )'z] The average ionic weight= g Observedcyroscopic weight: 126.4

PROPERTIES Appearancea white granular solid Solubility at 23 C.-c. 3%w./v. pH of solution-the pH of a c. 3% solution is 6.0

REACTION WITH SODIUM HYDROXIDE When treated in the cold with 3 N NaOH,ammonia is freely evolved.

Example 12 The preparation of a potassium hydroxoaluminate chelatecomposition of citric and salicylic acids.

MATERIALS USED G. Aluminium chloride hexahydrate (98%) 15.4 Citric acidmonohydrate 6.566 Salicylic acid 4.33 Potassium hydroxide 5.26

The method of preparation was similar to that given for Example 11,substituting potassium hydroxide for ammonium hydroxide at Stage 4.

AVERAGE FORMULA IN MONOMERIC FORD/I 1.5[ 6 4 7)O.5'(S%' 523)D.S( )1.5( 21.5]

STRUCTURE.-APPROXIMATE ESTIMATE OF DEGREE OF POLYMERISATION Thecryoscopic estimate of average ionic weight=182.4 If x=the number ofaluminium ions in the complex anion This indicates an average degree ofpolymerization of 7. The compounds will comprise:

Observed cryoscopic estimate- 182.4

The average ionic Weight will be =182.7

PROPERTIES Appearancea white solid with slight pinkish tinge Solubilityat 23 C. l1 80% w./v. pH of solution-the 80% w./v. solution has a pH of7.6

Example 13 The preparation of an hydroxoaluminate chelate position oflactic acid and salicylic acid.

MATERIALS USED com- G. Dry sodium aluminate 93.8% (Na O:Al O =1.24)19.07

Sodium hydroxide 2.08 Lactic acid (88% w./v.) 20.48 Salicylic acid 27.62

PROCEDURE (1) A solution of the sodium aluminate was prepared andfiltered and then made up to 250 ml.

(2) 50 ml. of the sodium aluminate solution was added to the lactic acidwith stirring.

(3) Solid salicylic acid and sodium aluminate solution were addedalternately until all had been incorporated.

(4) The sodium hydroxide was added in solution.

(5) The solution was evaporated to dryness in vacuo at 60 C.

AVERAGE FORMULA IN MONOMERIC FORM ra[ 3 4 a)0.s( 7 4 3)o.5( )2.5( 2)1.5]

STRUCTURE.-APPROXI1\IATE ESTIMATE 0F DEGREE 0F POLYMERISATION Thecryoscopic estimate of average ionic weig-ht=137.18

If x=the number of aluminium ions in the complex anion This resultindicates a 4x polymer FORMULA s[ 4 a t a)2( 'z 4 'a)2( )1o] 2 972.4Average ionic weight= Observed cryoscopic weight= 137.18

PROPERTIES Appearance a dark cream coloured solid Solubility at 23 C.- t70% w./v. pH of solution-a 40% solution has a pH of 7.7

Example 14 The preparation of an hydroxoaluminate chelate composition ofgentisic acid and gluconic acid.

MATERIALS USED G. Dry sodium aluminate 93.8% (Na O:Al O 1.24) 19.07

Sodium hydroxide 2.08

Genltisic acid trihydrate 20.81

Glucono'delta-lactone 17.8

PROCEDURE (1) The procedure followed was identical with that shown inExample 1 substituting gentisic acid for aspirin.

AVERAGE FORMULA IN MONOMERIC FORM m 1 4 4)osgsg aig v)o.s( )2.5( 2 )1.5]

Average ionic weight= g =1743 Observed cyroscopio weight= 170.01

PROPERTIES Appearance-light brown granular solid Solubility at 23 C.1:60% w./v.

pH of solution-the pH of a 40% solution is 10.15

Example 15 The preparation of a magnesium hydroxoaluminate compositionof salicylic and gluconic acids.

MATERIALS USED G. Aluminium isopropoxide 25.53 Glucono-delta-lactone (1)22.25 Salicylic acid 17.27 Glucono-delta-lactone (2) 11.13 Magnesiumoxide 5.04

PROCEDURE (1) The aluminium isopropoxide 30 mesh) was added slowly to asolution of a glucono-delta-lactone (1) dissolved in 50 ml. of distilledwater at C. The mixture AVERAGE FORMULA IN MONOMERIC FORM PROPERTIESAppearance-white translucent platelets Solubility at 23 C.- t60% w./v.pH of solution40% solution has a pH of 5.22.

Example 16 The preparation of a calcium hydroxoaluminate composition ofsalicylic and gluconic acids.

MATERIALS USED G. Aluminium isopropoxide 25.53 Glucono-delta-lactone (1)22.25 Salicylic acid 17.27 Glucono-delta-lactone (2) 11.13 Calcium oxide7.02

PROCEDURE (1) The aluminium isopropoxide (30 mesh) was added slowly to asolution of the glucono-delta-lactone (1) dissolved in 50 ml. ofdistilled water at 80 C. The mixture was maintained at 80 C. withstirring until dissolution was complete.

(2) The glucono-delta-lactone (2) and the salicylic acid were slurriedtogether in c. 50 ml. of distilled Water at 80 C. and the calcium oxidewas added. Mixing was continued at 80 C. for about minutes.

(3) The maximum from stage 2 was added slowly to the solution from stage1 and the temperature was maintained at 80 C. until a clear solutionresulted.

(4) The solution from stage 3 was evaporated to dryness in vacuo at 60C.

AVERAGE FORBIULA IN LIONOBIERIC FORM:

PROPERTIES Appearance-a pinkish white solid Solubility at 23 C.-7.8%w./v. pH of a saturated solution4.9.

Example 17 The preparation of an analgesic syrup containing 7.3 grainsaspirin per teaspoonfull (4 m1.) dose.

MATERIALS USED PER LITRE OF PRODUCT G. Dry sodium aluminate 93.8% (NaO:Al O =1.24) 125 Aspirin 118 Glucono-delta-lactone 117 Sucrose 415PROCEDURE (4) The aspirin was now stirred into the clear solution andwhen dissolved the sugar was added with further stirring.

Finally, when dissolution was complete the syrup was suitably colouredand flavoured and the volume was made up to 1 litre with water. Theresulting syrup was quite palatable and contained 7.5 grains of aspirinto the teaspoonful (4 ml.) dose.

The ability of the syrup to buffer the acid gastric juice was estimatedby the antacid activity test of Gore, Martin and Taylor (J. Pharm.Pharmacol., 1953, 5, 686691) modified to use a 4 ml. dose. It was foundon this test that the highest pH reached was 4.9 and that 11 ml. of NHCl were neutralized to pH 3. This is an acid neutralizing capacity fora one teaspoonful dose superior to that of many liquid antacidscurrently marketed.

Example 18 The preparation of an effervescent saline mixture containing5 grains of aspirin to the unit dose.

MATERIALS USED 2 parts by weight of a compound prepared from:

G. Dry sodium aluminate 93.8% (Na O:Al O =1.24) 125Glucono-delta-lactone 152 Aspirin 117 1.6 parts by weight of a granulargrade of sodium bicarbonate, 1.4 parts by weight of a crystalline gradeof tartaric acid. The dry components were thoroughly blended and packedinto sachets each containing a quantity of 5 g. of the mixture. Eachsachet therefore. contained, on the average,

G. Analgesic compound 2 Sodium bicarbonate 1.6 Tartaric acid 1.4

When the contents of a sachet were added to a tumbler one third filledwith water, a vigorous effervescence ensued, leaving a clear solutionwithout scum. The flavour was considered to be very palatable and eachdose contained the equivalent of 5 grains of aspirin.

Example 19 The preparation of a mixed acetatosalicylatogluconatoferrate.

MATERIALS USED G. Ferrous sulphate hepta hydrate 69.51 Sodium carbonate26.5 Glucono-delta-lactone 44.5

Aspirin 22.52 Sodium hydroxide 30.0

PROCEDURE The ferrous sulphate was dissolved in about 300 ml. of waterand the sodium carbonate dissolved in an equal amount of water was addedto precipitate ferrous carbonate. The ferrous carbonate was washed byrepeated decantation and then the glucono-delta-lactone, dissolved in200 ml. of water, was added followed by the aspirin in severalincrements. Finally, at the completion of dissolution the sodiumhydroxide, dissolved in about ml. of water, was added. The solution wasevaporated to dryness at 60 C. in vacuo.

PROPERTIES Appearanceolive-green, non-crystalline solid. Solubility at23 C.: about 3% NB. The solution, as first prepared, was about 10% andthis was concentrated to a clear syrup before the solid substanceseparated out. This solid substance proved to be less soluble, althoughthe solution may again be concentrated.

pH of a 10% solution: 12.25

21 Example 20 The preparation of sodiumgluconatosalicylatodiaquoaluminate III.

MATERIALS USED Aluminium isopropoxide 20.42

Glucono-delta-lactone (99%) 18.00

Salicylic acid 13.81

Sodium hydroxide 4.00

PROCEDURE (1) The aluminium isopropoxide (30 mesh) was added slowly to asolution prepared by dissolving the gluconodelta-lactone in 50 ml. ofdistilled water at 80 C. The mixture was maintained at 80 C. withstirring until dissolution was complete.

(2) The sodium hydroxide was dissolved in 30 ml. of water at about 30 C.and the salicylic acid was dissolved in this solution.

(3) The solution prepared in stage 2 was added to the solution preparedin stage 1.

The solution of the compound sodium gluconatosalicylatodiaquoaluminateIII, prepared as described, was found to have only a limited stability,but a further addition of 1.4% of sodium hydroxide (calculated on thedry compound weight) stabilized the solution and enabled it to beprepared in dry form by evaporating in vacuo at 60 C.

FORMULA Na [AIIHCGH1QO7.C7H4O3- molecular weight 416.23

n-orr-o Hi0 0-0 I Na l o=o-o mo 0 As a result of the addition of theextra sodium hydroxide the composition comprised a mixture ofpredominantly the monosodium compound and a small amount of the nexthigher hydroxo analogue-the disodium compound. A second preparationcarried out in more dilute solution (total water 120 ml.) was successfulwithout the additional sodium hydroxide.

PROPERTIES Appearance: white granular solid Solubility at 23 C.: 50%w./v. pH of solution: (a) with additional sodium hydroxide 5.5; (b)without additional sodium hydroxide 4. 65

Example 211 The preparation of disodiumacetatogluconatosalicylato-aquoaluminate III.

MATERIALS USED G Aluminium isopropoxide 20.42 Glucono-delta-lactone(99%) 18.00 Aspirin 18.02 Sodium hydroxide 8.00

PROCEDURE 1) The aluminium isopropoxide (30 mesh) was added slowly to asolution prepared by dissolving the gluconodelta-lactone in 50 ml. ofdistilled water at 80 C. The mixture was maintained at 80 C. withstirring until dissolution was complete.

(2) The sodium hydroxide was dissolved in 50ml. of water at 30 C. Theaspirin was dissolved in this solution.

(3) The solution prepared in stage 2 was added to the solution preparedin stage :1.

(4) The solution was evaporated in vacuo at about 60 C. to produce thesolid compound.

FORMULA Nag ['A1 (C H1 O7 07 E403 molecular weight 480.29

PROPERTIES Appearance: white granular solid Solubility at 23 (3.: 60%w./v. pH of 10% solution: 5.15

Example 22' Materials required for 1 g./mol. of Compound I:

95.29 g. of sodium aluminate having a 93 .80% content of material ofmolecular ratio Na O/Al O =1:1.24

180.16 g. of acetylsalicylic acid 359.90 g. of glucono-delta-lactone(99%) 109.41 g. of sodium hydroxide.

The sodium aluminate was stirred in 150 ml. of water for thirty minutes.Meanwhile, 20% of the glucono-del'talactone (71.98 g.) was agitated in100 ml. of water until dissolved. Then the .gluconic acid solution wasadded to the sodium aluminate solution.

Then 30% of the solid acetylsalicylic acid (54.05 g.) was dissolved inthe solution, care being taken to stir vigorously and theacetylsalicylic acid not. being added too rapidly. When dissolved, about15 g. of Hyflo Supercel filter-aid was added, and filtered while stillwarm. The rest of the glucono-delta-lactone (287.92 g.) dissolved in ml.of water was added.

With constant stirring the remainder of the acetylsalicylic acid (126.11 g.) was added gradually to the sodium hydroxide in ml. water. Thesecond solution was added to the first solution with constant stirring,and the mixture was evaporated to dryness (constant weight) in vacuo at70 C.

This gave an odourless, off-white, non-crystalline solid with a sharpflavour, having the properties:

Solubility in water at 25: C. 80% w./v.

Insoluble in either, chloroform, benzene, alcohol and carbontetrachloride pH of 40% solution=7.10

The 40% solution is clear, straw coloured, and has a slightly sourodour.

Acid neutralizing capacity:

'1 gramme (dry basis) in 200 ml. of water required 5.4

ml. N.l1ydrochloric acid to reduce to pH 3.

Specific rotation: +305 Ultra-violet absorption Wavelength Max. or Min.E 1% 1 cm.

i 230 m Maximum 98.09 259 my. Minimum 6. 45 297 m Maximum 49 50 Example23' The preparation of a flavoured analgesic syrup. The followingmaterials were taken:

Percent w./v. Dry sodium aluminate 93.8%

(Na O:Al O =1.24) 6.347 Glucono-delta-lactone 22.241 Acetylsalicylicacid 12.000 Sodium hydroxide 6.807 Sucrose 40.000

Colour and flavour q.s.

The dry sodium aluminate was suspended in about 20% of the availablewater and stirred for 30 minutes. To this suspension was added 20% ofthe glucono-deltalactone dissolved in a further 20% of the water. About30% of the solid acetylsalicylic acid was then dissolved in thesolution. The remaining glucono-delta-lactone was dissolved in 40% ofthe water (warm) and the solution was added to the one already prepared.The remainder of the acetylsalicylic acid was dissolved in a solution ofthe sodium hydroxide in the rest of the water and this was added to themain bulk. The temperature was maintained at about 80 C. for 30 minutes.After filtration through a prepared bed, the sugar was dissolved in thesolution and any colours and flavours were added. The resulting productcontained the equivalent of 10 gr. of acetylsalicylic acid in ml. ofsyrup.

Compound I is a buffer antacid as well as being an analgesic compound.It was found that 5 ml. of product when examined by the test of Gore,Martin & Taylor (Ref.: J. Pharm. Pharmacol. 5, 686-691, 1953)neutralised 12.0 ml. N.hydrochloric acid to pH 3, the peak pH being 5.2.

Example 24 The preparation of an effervescent granular product.

The following materials were taken to prepare 100 g. of effervescentgranules:

G. Alfloc Dry sodium aluminate 6.342 Acetylsalicylic acid B.P. 11.990Glucono-delta-lactone 23.952 Sodium hydroxide B.P. 7.282 Citric acidmonohydrate B.P. 5.926 Tartaric acid B.P. 20.828 Sodium sesquicarbonatedihydrate 28.162

Sweetener and flavour q.s.

A solution of Compound I was prepared as described in Example 2 (i.e. upto the stage before the addition of the sucrose). The syrupy solutionwas then evaporated to dryness in a vacuum evaporator, a light, flakysolid being obtained.

The citric and tartaric acids and half the sesquicarbonate were blendedand allowed to stand without mixing for a few minutes; this resulted ina slightly doughy mass. Compound I and the remaining sodiumsesquicarbonate (with which were incorporated any sweetener and flavour)were added in alternate increments to the mass and mixing was thenresumed to the stage of a well formed granule. The granules were driedat 50 C.

A product was obtained in which the available carbon dioxide was of theorder of 5 g. dissolving in a draught of water to give a clear solutioncontaining the equivalent of 10 gr. of acetylsalicylic acid. Theemployment of sodium sesquicarbonate both facilitated the granulationprocess and gave a product having exceptionally good solubilitycharacteristics.

Example 25 The preparation of an effervescent analgesic tablet.

G. Compound I a- 350.00 Citric acid monohydrate 96.43 Tartaric acid304.11 Sodium sesquicarbonatedihydrate 411.14

Sweetener and flavour q.s.

Granulation was elfected by the method described in Example 3. The driedgranules were passed through a 30 mesh sieve and blended with 2% ofpolyethylene glycol 4000 lubricant. The mixture was compressed to give 4g. tablets containing the equivalent of 5 gr. of acetylsalicyclic acid.

24 Example 26 The preparation of a soluble, flavoured, analgesic powder.

G. Compound I 70.000 Sodium sesquicarbonate dihydrate 3.948 Tartaricacid 3.835 Sucrose 5.525 Sodium cyclamate 4.144 Flavour q.s.

and dimers thereof wherein M is magnesium, calcium, sodium, potassium orthe ammonium radical, M is aluminium, magnesium, iron or calcium, and A0is the salicylato bidentate ion:

or the S-hydroxysalicylato ion, together with at least 5% of an ion orions selected from the group consisting of the bidentate ions formedfrom the monocarboxylic al pha-hydroxy acids of the formula:

[midi in which R is CH or r r l -ti r OH H OH H and the tetradentateions formed from tartaric and citric acids of the respective formulae:

wherein x is an integer from 1 to 5 inclusive, Y is 1 or 2, w is aninteger from 0 to 4 inclusive, z is an integer from 1 to 4 inclusive, nis 2 for bidentate ions when the valency of M is greater than 1 and isunity in all other cases, I is the valency of M divided by n, m is thevalency of M and v is an integer from 0 to 6 inclusive.

25 2. The compound of the formula 3. A process for preparing thecompounds claimed in References Cited claim 1, which process comprisesreacting in solution, 20 UNITED STATES PATENTS acid, neutral or basicalpha-hydroxy acid salts of the metals M and M.

3,100,787 8/1963 Staib 260448 3,200,136 7/ 1963 Grassmith. 1,967,649

4. A process as claimed in claim 3, wherein the acid, 7/1934 Wolf 2 0neutral or basic a-hydroxy acid salts are prepared in situ 25 2,327,815

8/ 1943 Niedercorn et al. 260-448 from the metals or their oxides,hydroxides, .alkoxides or 2,874,177 2/ 59 Hayano 260-448 carbonates andthe appropriate hydroxy acids.

OTHER REFERENCES Burrows and Wark, Chemical Society Journal, Janu- 5. Aprocess as claimed in claim 1 for preparing compounds in which M is analkali metal and M is aluminium, 30 ary-Iune 1928, pp. 226 and 227.wherein there are brought together in solution an alkali ChemicalAbstracts, vol. 53, PP- 4757g: 1959- metal aluminate and one or more ofthe acids acetylsali Chemical Abstracts, 8, PP 6142: 1914- cylic acid,salicylic acid and S-hydroxysalicylic acid, and Chemlcal Abstracts 836%1956' one or more of the acids lactic, gluconic, citric and tar- TOBIASLEVOW, Primary Examiner'- taric acids.

35 H. M. S. SNEED, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,391,176 July 2 1968 Frederick Grossmith It is certified that error appearsin the above identified patent and that said Letters Patent are herebycorrected as shown below:

In the heading to the printed specification, under line 12, insertClaims priority, application Great Britain, Apr. 24, 1962, 15,429/62;Aug. 10, 1959, 27,330/59 Column 5, line 32,"salicylatogluconatodihydroxodiaque" should readsalicylatogluconatodihydroxodiaquo Signed and sealed this 30th day ofDecember 1969.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Commissioner of Patents Edward M. Fletcher, In,

Attesting Officer

